Medicinal mixture for alleviation of painful conditions and method for using same

ABSTRACT

A COMPOSITION COMPRISING (+)-1-BENXYL-3-DIMETHYLAMINO-2-METHYL-1-PHENYLPROPYLPROPIONATE (I) ADMIXED WITH A COMPOUND SELECTED FROM THE GROUP CONSISTING OF 2-CHLORO-9-($ - DINETHYLAMINOPROPYLIDENE)-THIOXANTHENE (II), 2 - CHLORO-9-(3-(N&#39;&#39;-B-HYDROXYETHYLPIPRAZINO)-PROPYLIDENE)-THIOXANTHENE (III) AND 2-TRIFLUOROMETHY-9-(3(N&#39;&#39;-B-HYDROXYETHYLPIPERAZINO)-PROPLIDENE)-THIOXANTHENE (IV). SPECIFIC COMPOSITIONS ARE THOSE IN WHICH THE WEIGHT RATIOS OF THE COMPONENTS AND IN THE CASE OF I AND II, AND I AND III, FROM 1:1 TO 64:1, AND IN THE CASE OF I AND IV FROM 1:1 TO 200:1. THE COMPOSITIONS MAY BE ADMINISTERED IN DOSAGE UNIT FORM. THE ANALGESIC EFFECT OF I AND II, III OR IV IS MORE THAN ADDITIVE, BUT THE SEDATIVE EFFECT OF II, III OR IV IS NOT SUBSTANTIALLY AFFECTED.

United States Patent C 3,662,073 MEDICINAL MIXTURE FOR ALLEVIATION F PAINFUL CONDITIONS AND METHOD FOR USING SAME Dietrich Lorenz, Bensberg, Germany, assignor to Troponwerke Dinklage & Co., Cologne-Mulheim, Germany No Drawing. Filed Apr. 24, 1969, Ser. No. 819,535

Claims priority, application Germany, Apr. 30, 1968, P 17 67 344.8 Int. Cl. A61k 27/00 U.S. Cl. 424-250 4 Claims ABSTRACT OF THE DISCLOSURE A composition comprising (+)-l-benzyl-3-dimethylamino-2-methyl-l-phenylpropylpropionate (I) admixed with a compound selected from the group consisting of 2-Chl01'O-9-(y dimethylaminopropylidene)-thioxanthene (II), 2 chloro-9-[3-(N'-;8-hydroxyethylpiperazino)-propylidene]-thioxanthene (III) and 2-trifluoromethyl-9-[3- (N-;8-hydroxyethylpiperazino) -propylidene] -thioxanthene (IV). Specific compositions are those in which the weight ratios of the components and, in the case of I and II, and I and III, from 1:1 to 64:1, and in the case of I and IV from 1:1 to 200:1. The compositions may be administered in dosage unit form. The analgesic efiect of I and II, III or IV is more than additive, but the sedative effect of II, III or IV is not substantially aifected.

This invention relates to a medicinal mixture for alleviation of painful conditions in subjects including human subjects.

Since the introduction of modern psychopharmocological agents e.g. derivatives of the thioxanthene, phenthia- Zine and butyrophenone series, in the therapy of mental disorders and other disturbances or defects of regulation caused by the central nervous system, such agents have also been introduced to an increasing degree for the alleviation of pain. However, this has been done more to assist the action of other specific analgesics, by a psychic shield against the occurrence of pain (see for example H. Linke, Symposium for Pharmacopsychiatry and Psychopharmacology Karloy Vary, 2-5X, 1967), rather than because of the weak direct analgesic elfect which the cmopounds possess.

Consequently in practice, such psychopharmacological agents have so far been arbitrarily combined with strongly acting analgesics, without the actual combinations having been matched to one another as regards elfective strength and dosage.

As a result of a systematic investigation of the action of combination of analgesic and such psychopharmacological agents it has been found that the strongly acting analgesic 1 benzyl-3-dimethylamino-=2-methyl-lphenylpropyl-propionate (hereinafter referred to as I), combined with at least one of the following psychopharmacological agents:

2-ch1010-9-('y dimethylaminopropylidene)-thioxanthene (hereinafter referred to as II),

2-chloro-9-[3-(N' B hydroxyethylpiperazino)-propylidene]-thioxanthene (hereinafter referred to as III) and 2-trifluoromethyl-9-[3-(N' 13 hydroxyethylpiperazino)- propylidene]-thioxanthene (hereinafter referred to as W).

when used in analgesic tests on a mouse, exhibits a more than additive increase in efiect which is two to three times greater than additive. Consequently, doses two to three times smaller are necessary with the combinations in order to produce the same analgesic action. The ED 3,662,073 Patented May 9, 1972 values of compounds I to IV are set out in Table 1, these having been established by the hot-plate test and the henzoquinone test on the mouse. The EDs values are defined as the doses which, with a single oral administration 30 minutes before initiating the heat stimulation (hotplate) or the chemical stimulation on the peritoneum (benzoquinone), completely inhibits the pain reaction with 50% of the animals.

TABLE 1 Hotplate Benzoqui- EDso, none EDso, Substance rug/kg. mg-l Tables 2 and 3 set out the results of combination tests, which were found when combining the aforementioned psychopharmacological agents with I in the two tests r eferred to. These combination tests were carried out in accordance with the data given by Dr. Lorenz and E. Miiller (Arzneimittelforschung 17 (1967), page 229). By way of example the results are given for a combination of 4 and 8 parts by weight of I with one part of the corresponding psychopharmacological agent.

In the two tables:

Column 1 indicates the actual combination of substances,

Column 2 indicates the theoretical ED values, which can TABLE 2.-HOTPLATE Substance Theoretical EDsn Experimental EDso A B Comp: A Comp. B Comp. A Comp. B Quotient II I- 7. 56 30. 24 3. 28 13. 1 2. 31 III I- 9. 25 36. 92 4. 05 16. 21 2. 28 IV 1...- 11.05 44. 21 4. 88 19.5 2.27

TABLE 3.-BENZOQ,UINON E Substance Theoretical EDso Experimental ED A B Comp. A Comp. B Comp. A Comp. B Quotient II 1--.. 1.21 4.84 0.7 2.8 1.73 III 1---. 2. 77 11. O8 1. 86 7. 46 1. 49 IV I 3.3 26 1.88 15 1.73

1 In the ratio 1 :8.

The invention is thus concerned with a pharmacological mixture of active substances with particularly increased analgesic action, which is characterised in that it contains the compound ('+)-l-benzyl-3-dimethylamino-2-methyll-phenylpropylpropionate (I) admixed with 2-chloro-9-'ydimethylaminopropylidene)-thioxanthene (H), 2-chloro- 9-[3-(N'-fl-hydroxyethylpiperazino) propylidene] thioxanethene (III) or 2-trifluoromethyl-9[3-(N-}8hydroxyethylpiperazino)-propylidene]-thioxanthene (IV).

The more than additive increase in the analgesic effect of I by the compounds II to IV as indicated is not only to be found in the mixing ratio given in the tables, but extends over a quite specific range of combination with each psychopharmacological agent, as follows:

IIzI, from 1:1 to 1:64 11121, from 1:1 to 1:64 IV:I from 1:1 to 1:200

The super-additive combination effect which has been found concerns only the analgesic action of I, but not the neuroleptic sedative action of the psychopharmacological agents. Thus, in the combination tests carried out by the same procedure, it was found that the balancing ability of mice, which is influenced by such agents even in very small doses, cannot be super-additively inhibited in the same manner when II-IV are combined with I. Accordingly, the strengthening of the analgesic action of I by such agents isr not accompanied by a simultaneous strengthening of the neuroleptic-sedative action when the materials are mixed in the specified ratios. The strengthening of analgesic action which is therapeutically important is thus not limited by an increase in the sedative action.

The intensification of the action of I which We have found, without an increase in the sedative elfect, is obviously a specific property of II, III and IV, which apparently other psychopharmacological agents do not possess. By way of example, a combination of I with the therapeutically widely dispensed neuroleptic 2-chloro-10- (3-dimethylarninopropyl)-phenthiazine in the ratio 1:2 to 1:8 has only a purely additive effect in both of the tests described. The thymoleptic agent 5-('y-dimethylaminopropylidene)--hereinafter referred to as V, or the agent 5- (y-methylaminopropylidene) 5H dibenzo-(a,d) (1,4)- cyclopentadiene, to which an independent analgesic action has been ascribed (see K. Opitz and V. Borchert, Klin. Wschr. 45 (1967), page 887), does not show any super-additive eifect when combined with I in the hotplate test. It is only in the benzoquinone test that V superadditively increased the action of I, but in this case, by contrast with II, III and -IV, the sedative effect increased to the same extent.

The following information can be given regarding dosages which can be used in practice for the administration of the new mixtures of active substances according to the invention:

As regards mixture I+II, 35-70 mg. of I and 5-50 mg. of-II canbe combined in one dose, while with mixture I-l-III, 5-30 mg. of III, and with mixture I+IV, 0.2-2.5 mg. of IV, can be used in each case with 35-70 mg. of I per dose.

The mixtures according to the invention can be formulated for administration in association with an inert pharmaceutically acceptable carrier which may be liquid, semi-liquid or solid as desired. The composition may be in a form suitable for oral administration and thus may be in the form of tablets, capsules, elixirs or the like. A preferred form of administration is as a tablet containing a specific dose, preferably within the ranges specified above for the particular agents in question. The pharmacuetical compositions may also. be administered by the parenteral route, as injectable solutions and the invention extends to such solutions, particularly containing a dose of the active substances in the range specified above in a predetermined quantity of non-pyrogenic water.

I claim:

1. A composition suitable for use as analgesic comprising -1-benzyl-3-dimethylamino-2-methyl-l-phenylpropylpropionate (I) admixed with 2-trifiuoromethyl-9- (3 (N-fi-hydroxyethylpiperazino)-propylidene)-thioxanthene (IV), the proportions of (I) to (IV) being in a weight ratio of 1:11 to 200:1.

2. A composition suitable for use as an analgesic comprising -1-benzyl-3-dimethylamino-2-methyll-phenylpropylpropionate (I) admixed with 2-trifluoromethyl-9- (3 (N'-;9-hydroxyethylpiperazino)-propylidene)-thioxanthene (IV) and an inert pharmaceutically acceptable carrier, the proportion of ,(I) to (IV) being in a weight ratio of 1:1 to 20011.

3. A composition as claimed in claim 1 in tablet form.

4. A method of alleviating painful conditions in a human subject which comprises the administration to said subject of a therapeutically effective amount to produce an analgesic effect of a composition comprising (+)-lbenzyl 3 dimethylamino-Z-methyl-l-phenylpropylpropionate (I) admixed with 2 trifluoromethyl-9-(3-(N-/3- hydroxyethylpiperazino)-propylidene)-thioxanthene (IV), the proportion of (I) to ,(IV) being in a weight ratio of 1:1 to 200:1.

References Cited American Drug Index, 1968, p. 172. Psychopharmacological Agents, vol. 1, Gordon. Medicinal Chemistry, A Series of Monographs, pp. 301-302, 315-322.

Merck Index, 7th ed. (1969), p. 862.

STANLEY J. FRIEDMAN, Primary Examiner US. Cl. X.R. 424-276, 31 1 

